Mouse schwann cells need both NRG1 and cyclic AMP to myelinate

Abstract

Genetically modified mice have been a major source of information about the molecular control of Schwann-cell myelin formation, and the role of β-neuregulin 1 (NRG1) in this process in vivo. In vitro, on the other hand, Schwann cells from rats have been used in most analyses of the signaling pathways involved in myelination. To correlate more effectively in vivo and in vitro data, we used purified cultures of mouse Schwann cells in addition to rat Schwann cells to examine two important myelin-related signals, cyclic adenosine monophosphate (cAMP), and NRG1 and to determine whether they interact to control myelin differentiation. We find that in mouse Schwann cells, neither cAMP nor NRG1, when used separately, induced markers of myelin differentiation. When combined, however, they induced strong protein expression of the myelin markers, Krox-20 and P(0) . Importantly, the level of cAMP signaling was crucial in switching NRG1 from a proliferative signal to a myelin differentiation signal. Also in cultured rat Schwann cells, NRG1 promoted cAMP-induced Krox-20 and P(0) expression. Finally, we found that cAMP/NRG1-induced Schwann-cell differentiation required the activity of the cAMP response element binding family of transcription factors in both mouse and rat cells. These observations reconcile observations in vivo and on neuron-Schwann-cell cultures with studies on purified Schwann cells. They demonstrate unambiguously the promyelin effects of NRG1 in purified cells, and they show that the cAMP pathway determines whether NRG1 drives proliferation or induces myelin differentiation.

The Role of Neuregulin-1 In the Response To Nerve Injury

“…One example is Notch signaling, which promotes the survival and proliferation of SCPs, increases the expression of erbB2 in SCPs and enhances their sensitivity to NRG1 [61]. At later stages of SC development, in order for myelination to proceed, there is an important interaction between cAMP and NRG1 signaling (see later) [62].…”

“…An as-yet unidentified axonal ligand activates GPR 126, which is expressed on SCs, leading to increased cAMP, which is critical for myelination [68]. NRG1-induced expression of Krox 20 and myelin-related proteins in mouse SCs requires the presence of elevated cAMP [62].…”

“…Crucially, cAMP appears to switch NRG1 from a proliferative signal to a myelin differentiation signal [62]. A further example of interaction between these pathways is that type III NRG1 and cAMP-dependent PKA phosphorylation act cooperatively to increase the activity of NF-κB, which promotes myelination [69,70].…”

“…One example is Notch signaling, which promotes the survival and proliferation of SCPs, increases the expression of erbB2 in SCPs and enhances their sensitivity to NRG1 [61]. At later stages of SC development, in order for myelination to proceed, there is an important interaction between cAMP and NRG1 signaling (see later) [62].It was previously thought that the promotion of myelination by NRG1 type III/erbB signaling was mediated primarily via the PI3K/Akt pathway. Crucially, cAMP appears to switch NRG1 from a proliferative signal to a myelin differentiation signal [62].…”

“…At later stages of SC development, in order for myelination to proceed, there is an important interaction between cAMP and NRG1 signaling (see later) [62].…”